I. Field of the Invention
The invention relates to the fields of molecular and cellular biology and oncology, and particularly to the treatment of cancers that involve the overexpression of thromboxane receptor β.
II. Related Art
Bladder cancer is the fifth most common cancer in the United States accounting for about 4.6% of all cases (Jemal et al., 2007). Most incidences of bladder cancer are superficial and localized in character with about 74% of all cases being localized when diagnosed (Jemal et al., 2007). It exists in two main forms, non-invasive which lacks invasion into surrounding muscle tissue and is the more common form accounting for 75% of all cases and muscle invasive in which it spreads into surrounding urinary areas and may metastasize (Sengupta and Blute, 2006).
The inventors have previously found that thromboxane synthase was over-expressed in patients with bladder cancer and was associated with a significantly poorer prognosis (Moussa et al., 2005). Thromboxane synthase catalyzes the formation of thromboxane A2 from prostaglandin H2, which is derived from the precursor arachidonic acid (Needleman et al., 1976). Thromboxane A2, although very labile, stimulates it receptors to produce a myriad of pharmacologic events (Halushka et al., 1989; Halushka et al., 1997; Halushka, 2000). Thromboxane A2 (TP) receptors are G protein coupled receptors (GPCR) and are expressed as two different isoforms, TP-α (Hirata et al., 1991) and TP-β (Raychowdhury et al., 1994), and arise by alternative mRNA splicing (Miggin and Kinsella, 1998). Stimulation of TP receptors is associated with a mitogenic response (Nagata et al., 1992). The isoforms share both common and different intracellular signaling mechanisms and different trafficking patterns. Both isoforms signal through Gαq resulting in transient increases in intracellular calcium and IP3 formation and through Gα12 to stimulate sodium-hydrogen exchange (Halushka, 2000; Becker et al., 1999; Shenker et al., 1991). When stimulated by ligand, TP-β, but not TP-α, couples to Gαi which decreases cAMP production (Hirata et al., 1994; Hirata et al., 1996). Stimulation of both receptors results in phosphorylation of ERK and FAK (Miggin and Kinsella, 2002; Gao et al., 2001). Nonetheless, the role of TP receptors in bladder cancer remains unclear.